Objectives are (1) to further develop diabetic nephropathy (DN) risk markers based on in vitro studies of cells derived from type 1 D patients (pts), (b) to ask if these markers represent genetically determined processes and (c) to determine if these predictors are dependent on in vivo cellular exposure to D. These markers will be searched for by (i) their relevance to known pathophysiologic patterns and by (ii) microarray screening for candidate molecules and discriminant expression patterns. Five groups will be studied: (1) early (10 yrs) and (2) long-term (20 yrs) D duration pts dichotomized into 2 groups with slow or rapid development of DN lesions and albuminuria, (3) sibling pairs concordant for type 1 D, (4) type 1 D kidney transplant recipients and their living donors, (5) type 1 D pts with rapid development of DN who have been cured of D by successful pancreas transplant for at least 5 yrs. DN will be quantitated morphometrically, and factored for duration or expressed as a rate determined by 2 biopsies 5 yrs apart. The primary endpoint will be mesangial volume fraction [Vv(Mes/glom)]. Cross-sectional studies of long-term pts will allow the identification of markers associated with DN risk. Longitudinal studies (5 yr) in shorter-term will determine if these markers are present before any increase in albuminuria is detectable. Skin fibroblasts (SF) were selected since differences in their phenotype occur between "slow-track," "fast-track" and controls and their phenotypes are correlated in sibling pairs. Proximal tubular epithelial cells (PTEC) are selected because tubular basement membrane changes in D parallel those in glomeruli. These studies will determine the relationship of DN to SF and PTEC behaviors (gene expression levels and patterns; cell proliferation cell cycle), and evaluate whether these behaviors are genetically regulated. These studies will provide markers and predictors of DN risk, determine if these are genetically regulated or dependent on prior exposure to D, and identify DN pathogenetic pathways.